Delayed development of coronary artery disease in premenopausal women, compared to that of age-matched men, was noted over sixty years ago (Levy et al, J. Am. MedAssoc. 107:97-102 (1936), Master et al, Arch. Int. Med. 64:767-786 (1939)). Despite numerous reports addressing the antiatherogenic effect of estrogen in premenopausal women and in postmenopausal women on estrogen replacement therapy, the mechanism of this protective effect and its relationship to alteration in serum lipids is still unclear.
Even less is known about the effect of progesterone on the development of atherosclerosis, either alone or in combination with estrogen. Conflicting clinical and experimental data suggest that the effect of exogenous progestogens on the development of coronary artery disease ranges from adverse (Hirvonen et al, N. Engl. J. Med. 304:560-563 (1981)) to null (Adams et al, Arteriosclerosis 10:19051 (19090)) to potentially desirable (Haarbo et al, Am. J. Med. 90:584-589 (1991)) to favorable (Alexandersen et al, Arterioscler Thromb. Vasc. Biol. 18:902-907 (1998)) when combined with estriol treatment. A favorable effect of progesterone treatment alone is not believed to have been documented in a clinical study.
Various animal models used to study the effects of sex steroids on the development of atherosclerosis have demonstrated beneficial results associated with exogenous estrogen with or without progesterone in chickens (Pick et al, Circulation 6:276-280 (1952), Pick et al, Circulation 4:468 (1951)), mice (Sullivan et al, J. Clin. Invest. 96:2482-2488 (1995)), rabbits (Kushwaha et al, Metabolism 30:359-366 (1981), Fischer et al, Atherosclerosis 54:177-185 (1985), Haarbo et al, J. Clin. Invest. 87:1274-1279 (1991), Hanke et al, Circulation 94:175-181 (1996), Holm et al, Circulation 98:2731-2737 (1998)), monkeys (Wagner et al, J. Clin. Invest. 88:1995-2002 (1991)), and baboons (Kushwaha et al, Arterioscler. Thromb. 11:23-31 (1991)). Spagnoli and coworkers (Spagnoli et al, Atherosclerosis 82:27-36 (1990)) reported for the first time that high-dose synthetic progestogens alone inhibited atherosclerotic plaque formation in female rabbits fed a cholesterol-enriched diet and concluded that the protective effect was only partly due to alteration in serum cholesterol.
The present invention results, at least in part, from the observation that aortic atherosclerotic plaque load can be decreased in hypercholesterolemic male rabbits with exogenous progesterone as well as with estriol, the decreases in plaque load being independent of alterations in serum lipid levels.